Single cell ATAC-seq identifies broad changes in neuronal abundance and chromatin accessibility in Down Syndrome

Abstract

AbstractDown Syndrome (DS) is caused by triplication of chr21 and is associated with cognitive impairment, Alzheimer’s Disease, and other developmental alterations. The Ts65Dn mouse model for DS has triplication of sequences syntenic with human chr21, and traits resembling those seen in humans with DS. We performed single-cell combinatorial indexing assay for transposase accessible chromatin using sequencing (sci-ATAC-seq) on cortices of adult Ts65Dn mice and control littermates. Analyses of 13,766 cells revealed 26 classes of cells. The most abundant class of excitatory neurons was reduced by 17% in Ts65Dn mice, and three of the four most common classes of interneurons were increased by 50%. Ts65Dn mice display changes in accessibility at binding motifs for transcription factors that are determinants of neuronal lineage, and others encoded within triplicated regions. These studies define previously uncharacterized cellular and molecular features of DS, and potential mechanisms underlying the condition.